Matthew J. Summers

Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: Relationship to glycemia

Objective:To determine the acute effects of exogenous glucagon-like peptide-1 on gastric emptying, glucose absorption, glycemia, plasma insulin, and glucagon in critically ill patients. Design:Randomized, double-blind, crossover study. Setting:Intensive care unit. Subjects:Twenty-five mechanically ventilated patients, without known diabetes, studied on consecutive days. Interventions:Intravenous glucagon-like peptide-1 (1.2 pmol/kg/min) or placebo was infused between −30 and 330 mins. At 0 min, 100 mL liquid nutrient (1 kcal/mL) including 100 &mgr;g of 13C-octanoic acid and 3 grams of 3-O-methyl-glucose was administered. Measurements and Main Results:Blood glucose, serum 3-O-methyl-glucose (as an index of glucose absorption), insulin and glucagon concentrations, as well as exhaled 13CO2 were measured. The gastric emptying coefficient was calculated to quantify gastric emptying. Data are presented as mean (sd). There was a nonsignificant trend for glucagon-like peptide-1 to slow gastric emptying (gastric emptying coefficient) (glucagon-like peptide-1, 2.45 [0.93] vs. placebo, 2.75 [0.83]; p = .09). In 11 of the 25 patients, gastric emptying was delayed during placebo infusion and glucagon-like peptide-1 had no detectable effect on gastric emptying in this group (1.92 [0.82] vs. 1.90 [0.68]; p = .96). In contrast, in patients who had normal gastric emptying during placebo, glucagon-like peptide-1 slowed gastric emptying substantially (2.86 [0.58] vs. 3.41 [0.37]; p = .006). Glucagon-like peptide-1 markedly reduced the rate of glucose absorption (3-O-methyl-glucose area under the curve0–330, 37 [35] vs. 76 [51] mmol/L/min; p < .001), decreased preprandial glucagon (at 0 min change in glucagon, −15 [15] vs. −3 [14] pmol/L; p < .001), increased the insulin/glucose ratio throughout the infusion (area under the curve−30–330, 1374 [814] vs. 1172 [649] mU/mmol/min; p = .041), and attenuated the glycemic response to the meal (glucose area under the curve0–330, 2071 [353] vs. 2419 [594] mmol/L/min; p = .001). Conclusions:Exogenous glucagon-like peptide-1 lowers postprandial glycemia in the critically ill. This may occur, at least in part, by slowing gastric emptying when the latter is normal but not when it is delayed.

The effects of critical illness on intestinal glucose sensing, transporters, and absorption.

Objectives:Providing effective enteral nutrition is important during critical illness. In health, glucose is absorbed from the small intestine via sodium-dependent glucose transporter-1 and glucose transporter-2, which may both be regulated by intestinal sweet taste receptors. We evaluated the effect of critical illness on glucose absorption and expression of intestinal sodium-dependent glucose transporter-1, glucose transporter-2, and sweet taste receptors in humans and mice. Design:Prospective observational study in humans and mice. Setting:ICU and university-affiliated research laboratory. Subjects:Human subjects were 12 critically ill patients and 12 healthy controls. In the laboratory 16-week-old mice were studied. Interventions:Human subjects underwent endoscopy. Glucose (30 g) and 3-O-methylglucose (3 g), used to estimate glucose absorption, were infused intraduodenally over 30 minutes. Duodenal mucosa was biopsied before and after infusion. Mice were randomized to cecal ligation and puncture to model critical illness (n = 16) or sham laparotomy (control) (n = 8). At day 5, mice received glucose (100 mg) and 3-O-methylglucose (10 mg) infused intraduodenally prior to mucosal tissue collection. Measurements and Main Results:Quantitative polymerase chain reaction was performed to measure absolute (human) and relative levels of sodium-dependent glucose transporter-1, glucose transporter-2, and taste receptor type 1 member 2 (T1R2) transcripts. Blood samples were assayed for 3-O-methylglucose to estimate glucose absorption. Glucose absorption was three-fold lower in critically ill humans than in controls (p = 0.002) and reduced by a similar proportion in cecal ligation and puncture mice (p = 0.004). In critically ill patients, duodenal levels of sodium-dependent glucose transporter-1, glucose transporter-2, and T1R2 transcript were reduced 49% (p < 0.001), 50% (p = 0.009), and 85% (p = 0.007), whereas in the jejunum of cecal ligation and puncture mice sodium-dependent glucose transporter-1, glucose transporter-2, and T1R2 transcripts were reduced by 55% (p < 0.001), 50% (p = 0.002), and 69% (p = 0.004). Conclusions:Critical illness is characterized by markedly diminished glucose absorption, associated with reduced intestinal expression of glucose transporters (sodium-dependent glucose transporter-1 and glucose transporter-2) and sweet taste receptor transcripts. These changes are paralleled in cecal ligation and puncture mice.

Glucose absorption and small intestinal transit in critical illness

Objectives: Although enteral nutrition is standard care for critically ill patients, nutrient absorption has not been quantified in this group and may be impaired due to intestinal dysmotility. The objectives of this study were to measure small intestinal glucose absorption and duodenocecal transit and determine their relationship with glycemia in the critically ill. Design: Prospective observational study of healthy and critically ill subjects. Setting: Tertiary mixed medical-surgical adult intensive care unit. Subjects: Twenty-eight critically ill patients and 16 healthy subjects were studied. Materials and Main Results: Liquid feed (100 kcal/100 mL), labeled with Tc-sulfur colloid and including 3 g of 3-O-methylglucose, was infused into the duodenum. Glucose absorption and duodenocecal transit were measured using the area under the 3-O-methylglucose concentration curve and scintigraphy, respectively. Data are median (range). Results and Discussion: Glucose absorption was reduced in critical illness when compared to health (area under the concentration curve: 16 [1–32] vs. 20 [14–34] mmol/L·min; p = .03). Small intestinal transit times were comparable in patients and healthy subjects (192 [9–240] vs. 168 [6–240] min; p = .99) and were not related to glucose absorption. Despite higher fasting blood glucose concentrations (6.3 [5.1–9.3] vs. 5.7 [4.6–7.6] mmol/L; p < .05), the increment in blood glucose was sustained for longer in the critically ill (&Dgr; glucose at t = 60; 1.9 [−2.1–5.0] mmol/L vs. −0.2 [−1.3–2.3] mmol/L; p < .01). Conclusions: Critical illness is associated with reduced small intestinal glucose absorption, but despite this, the glycemic response to enteral nutrient is sustained for longer. (Crit Care Med 2011; 39:1282–1288)

Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes

IntroductionGlucagon-like peptide-1 (GLP-1) attenuates the glycaemic response to small intestinal nutrient infusion in stress-induced hyperglycaemia and reduces fasting glucose concentrations in critically ill patients with type-2 diabetes. The objective of this study was to evaluate the effects of acute administration of GLP-1 on the glycaemic response to small intestinal nutrient infusion in critically ill patients with pre-existing type-2 diabetes.MethodsEleven critically ill mechanically-ventilated patients with known type-2 diabetes received intravenous infusions of GLP-1 (1.2 pmol/kg/minute) and placebo from t = 0 to 270 minutes on separate days in randomised double-blind fashion. Between t = 30 to 270 minutes a liquid nutrient was infused intraduodenally at a rate of 1 kcal/min via a naso-enteric catheter. Blood glucose, serum insulin and C-peptide, and plasma glucagon were measured. Data are mean ± SEM.ResultsGLP-1 attenuated the overall glycaemic response to nutrient (blood glucose AUC30-270 min: GLP-1 2,244 ± 184 vs. placebo 2,679 ± 233 mmol/l/minute; P = 0.02). Blood glucose was maintained at < 10 mmol/l in 6/11 patients when receiving GLP-1 and 4/11 with placebo. GLP-1 increased serum insulin at 270 minutes (GLP-1: 23.4 ± 6.7 vs. placebo: 16.4 ± 5.5 mU/l; P < 0.05), but had no effect on the change in plasma glucagon.ConclusionsExogenous GLP-1 in a dose of 1.2 pmol/kg/minute attenuates the glycaemic response to small intestinal nutrient in critically ill patients with type-2 diabetes. Given the modest magnitude of the reduction in glycaemia the effects of GLP-1 at higher doses and/or when administered in combination with insulin, warrant evaluation in this group.Trial registrationANZCTR:ACTRN12610000185066

Randomized double-blind crossover study to determine the effects of erythromycin on small intestinal nutrient absorption and transit in the critically ill

BACKGROUND The gastrokinetic drug erythromycin is commonly administered to critically ill patients during intragastric feeding to augment small intestinal nutrient delivery. However, erythromycin has been reported to increase the prevalence of diarrhea, which may reflect reduced absorption and/or accelerated small intestinal transit. OBJECTIVE The objective was to evaluate the effects of intravenous erythromycin on small intestinal nutrient absorption and transit in the critically ill. DESIGN On consecutive days, erythromycin (200 mg in 20 mL 0.9% saline) or placebo (20 mL 0.9% saline) were infused intravenously between -20 and 0 min in a randomized, blinded, crossover fashion. Between 0 and 30 min, a liquid nutrient containing 3-O-methylglucose (3-OMG), [13C]triolein, and [(99m)Tc]sulfur colloid was administered directly into the small intestine at 2 kcal/min. Serum 3-OMG concentrations and exhaled (13)CO2 (indices of glucose and lipid absorption, respectively) were measured. Cecal arrival of the infused nutrient was determined by scintigraphy. Data are medians (ranges) and were analyzed by using Wilcoxons signed-rank test. RESULTS Thirty-two mechanically ventilated patients were studied. Erythromycin increased small intestinal glucose absorption [3-OMG AUC360: 105.2 (28.9-157.0) for erythromycin compared with 91.8 (51.4-147.9) mmol/L · min for placebo; P = 0.029] but tended to reduce lipid absorption [cumulative percentage dose (13)CO2 recovered: 10.4 (0-90.6) compared with 22.6 (0-100) %; P = 0.06]. A trend to slower transit was observed after erythromycin [300 (39-360) compared with 228 (33-360) min; P = 0.07]. CONCLUSIONS Acute administration of erythromycin increases small intestinal glucose absorption in the critically ill, but there was a tendency for the drug to reduce small intestinal lipid absorption and slow transit. These observations have implications for the use of erythromycin as a gastrokinetic drug in the critically ill. This trial was registered in the Australian New Zealand Clinical Trials Registry as ACTRN 12610000615088.

Pantoprazole or Placebo for Stress Ulcer Prophylaxis (pop-up): Randomized Double-blind Exploratory Study*

Objectives:Pantoprazole is frequently administered to critically ill patients for prophylaxis against gastrointestinal bleeding. However, comparison to placebo has been inadequately evaluated, and pantoprazole has the potential to cause harm. Our objective was to evaluate benefit or harm associated with pantoprazole administration. Design:Prospective randomized double-blind parallel-group study. Setting:University-affiliated mixed medical-surgical ICU. Patients:Mechanically ventilated critically ill patients suitable for enteral nutrition. Interventions:We randomly assigned patients to receive either daily IV placebo or pantoprazole. Measurements and Main Results:Major outcomes were clinically significant gastrointestinal bleeding, infective ventilator-associated complication or pneumonia, and Clostridium difficile infection; minor outcomes included overt bleeding, hemoglobin concentration profiles, and mortality. None of the 214 patients randomized had an episode of clinically significant gastrointestinal bleeding, three patients met the criteria for either an infective ventilator-associated complication or pneumonia (placebo: 1 vs pantoprazole: 2), and one patient was diagnosed with Clostridium difficile infection (0 vs 1). Administration of pantoprazole was not associated with any difference in rates of overt bleeding (6 vs 3; p = 0.50) or daily hemoglobin concentrations when adjusted for transfusion rates of packed red cells (p = 0.66). Mortality was similar between groups (log-rank p = 0.33: adjusted hazard ratio for pantoprazole: 1.68 [95% CI, 0.97–2.90]; p = 0.06). Conclusions:We found no evidence of benefit or harm with the prophylactic administration of pantoprazole to mechanically ventilated critically ill patients anticipated to receive enteral nutrition. The practice of routine administration of acid-suppressive drugs to critically ill patients for stress ulcer prophylaxis warrants further evaluation.

Intrasubject variability of gastric emptying in the critically ill using a stable isotope breath test.

BACKGROUND AND AIMS Isotope breath tests are increasingly used to evaluate the effects of prokinetic drugs on gastric emptying. The aim was to assess intrasubject variability in gastric emptying, when using an isotope breath test in the critically ill. METHODS A retrospective analysis of data was undertaken in 12 patients who had gastric emptying measurements on consecutive days using a (13)C-octanoic acid breath test. The gastric emptying coefficient--GEC (a global index for the gastric emptying rate), and the t(50) (calculated time for 50% of meal to empty) were calculated, together with the coefficient of variability for these parameters. Data are mean (SD). RESULTS Neither GEC (day 1: 3.3 (0.8) vs. day 2: 3.1 (0.6); P = 0.31) nor t(50) (day 1: 127 (43) min vs. day 2: 141 (48) min; P = 0.46) were significantly different between the two days. Intrasubject variability was less for GEC (15.6%) than for t(50) (31.8%). CONCLUSION There is only modest intrasubject variability in GEC measurements using the (13)C-octanoic acid breath test in critically ill patients. As such, it may be an acceptable measurement tool to assess the effects of prokinetic drugs in this group.

Endogenous amylin and glucagon-like peptide-1 concentrations are not associated with gastric emptying in critical illness.

In health, the hormones amylin and glucagon‐like peptide‐1 (GLP‐1) slow gastric emptying (GE) and modulate glycaemia. The aims of this study were to determine amylin and GLP‐1 concentrations in the critically ill and their relationship with GE, glucose absorption and glycaemia.

The Effect of Exogenous Glucose-Dependent Insulinotropic Polypeptide in Combination With Glucagon-Like Peptide-1 on Glycemia in the Critically Ill

OBJECTIVE Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have additive insulinotropic effects when coadministered in health. We aimed to determine whether GIP confers additional glucose lowering to that of GLP-1 in the critically ill. RESEARCH DESIGN AND METHODS Twenty mechanically ventilated critically ill patients without known diabetes were studied in a prospective, randomized, double-blind, crossover fashion on 2 consecutive days. Between T0 and T420 minutes, GLP-1 (1.2 pmol/kg · min−1) was infused intravenously with either GIP (2 pmol/kg · min−1) or 0.9% saline. Between T60 and T420 minutes, nutrient liquid was infused into the small intestine at 1.5 kcal/min. RESULTS Adding GIP did not alter blood glucose or insulin responses to small intestinal nutrient. GIP increased glucagon concentrations slightly before nutrient delivery (P = 0.03), but not thereafter. CONCLUSIONS The addition of GIP to GLP-1 does not result in additional glucose-lowering or insulinotropic effects in critically ill patients with acute-onset hyperglycemia.

Occult upper gastrointestinal mucosal abnormalities in critically ill patients

The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes.